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High blood pressure
Why is high blood pressure so important?
Because it causes death!
Causes of mortality in the Slovak Republic
54.5
23.3
5.9
5.7
5.4
0 10 20 30 40 50 60
Cardiovascular diseases
Cancer
Accidents and poisoning
Respiratory diseases
GI diseases
%
Consequences of arterial
hypertesion
Jalta - 4. 2 1945
12 3
Winston Churchill (1)24.01.65
Hypertensive encephalopathy
+ dementia
Josif Stalin (3)05.03.53
Stroke
Franklin D. Roosevelt (2)12.04.45
Apoplex
Stroke, Renal insufficiency
Arterial hypertensionHistory
0
20
40
60
80
100
0 1 2 3 4 5
Years after diagnosis
Su
rviv
al
(%)
Gudbrandsson , Acta Med Scand
1981;210(Suppl):650
Farmer et al. , Arch Intern Med
1963;112:118
Keith et al. , Am J Med Sci
1939;196:332-343
AT1-Receptor-Blockers
Alpha-1-Blockers
1950
1960
1970
1980
1990
200
0
Diuretics
Beta Blockers
Reserpine
(1949)
Captopril
(1981)
Losartan (1995)
Verapamil (1963)
Calcium Antagonists
Nifedipine (1975)
ACE-Inhibitors
Propranolol
(1965)
Furosemide
(1964)
Prazosin (1977)
HCTZ (1958)
Direct Renin InhibitorsAliskiren
(2007)
CV continuum
CV continuum
Hypertension
Diabetes
Dyslipidaemia
Central Obesity
Arteriosclerosis
Vascular remodeling
LVH
> IM thickness
Lacunar infarcts
Microalbuminuria
MI, AnginaStrokeCongestive Cardiac FailureRenal FailurePeripheral Artery Disease Non-fatal
recurrent
events
CHF
CRF
Dialysis
Dementia
GenesLife style Death
Modified after Dzau et al. Circulation 2006;114:2850-2870
Stop or delay the
progression
of vascular disease
† Survival for 75-yr-olds. Roger et al JAMA 2004‡ Brenner H Lancet 2002
Men WomenSurvival%
100
80
60
40
20
0
Time (year)0 1 2 3 4 5 6 7 8 9 10
Time (year)0 1 2 3 4 5 6 7 8 9 10
1996-2000
Prostate cancer† Breast cancer‡
1991-19951985-19901979-1984
5-year survival after heart failure
diagnosis in men and women
Survival%
100
80
60
40
20
0
BP determinants
Blood pressure determinants
BP = Flow x Peripheral resistance
Cardiac output = Stroke volume x Heart rate
Preload Contractility Afterload
Venous compliance
Compliance of large arteries
Inner diameter of resistant arteries
IVF volume
Na+ content Renal excretory capacity
Sympathetic Renin Ang II Aldosterone
Parasympathetic Local vasodilators (NO)
Blood pressure regulation
Central► Centers in mesencefalon and medulla oblongata afferented from superior
centers (cortex, limbic system via hypothalamus) and from baroceptors withefferentation to sympathetic and parasympathetic nervous system
• Baroreflex (Hypotension activates sympathetic nervous system)• Bainbridge reflex (High ventricular filling activates sympathetic)• Acute stress reaction
► Renin-angiotensin-aldosterone system• Chronic stress reaction
Local► Myogenous (Protective vasoconstriction)► Metabolic (Metabolic products induce dilation – renal adenosine causes
constriction)► Humoral (NO, EDHF vs. ET, EDCF)► Neurogenous (Axon reflex)
Impaired BP regulation:
Hypertension Repeatedly increased blood pressure over 160/95 mm Hg (borderline hypertension
over 140/90 mm Hg), however the value is arbitrary
Types:
► Unstable
► Fixed
► Non-dipping
Pathophysiology :
► Hyperdynamic
► Hyperresistant
Etiology:
► Primary
► Secondary
Renal hypertension
BP = Flow x Peripheral resistance
Cardiac output = Stroke volume x Heart rate
Preload Contractility Afterload
Venous compliance
Compliance of large arteries
Inner diameter of resistant arteries
IVF volume
Na+ content Renal excretory capacity
Renin Ang II AldosteroneRenal ischemia
Decreased Na load in DT Renal parenchyma reduction (glomerulonephritis, gestational
nephropathy)
Tumor producing renin
Endocrine hypertension
BP = Flow x Peripheral resistance
Cardiac output = Stroke volume x Heart rate
Preload Contractility Afterload
Venous compliance
Compliance of large arteries
Inner diameter of resistant arteries
IVF volume
Na+ content Renal excretory capacity
Sympathetic Aldosterone
Phaeochromocytoma
Glucocorticoids MineralcorticoidsCushing syndrome
Adrenogenital syndrome ACTH
Conne syndrome
Neurogeneus hypertension
BP = Flow x Peripheral resistance
Cardiac output = Stroke volume x Heart rate
Preload Contractility Afterload
Venous compliance
Compliance of large arteries
Inner diameter of resistant arteries
IVF volume
Na+ content Renal excretory capacity
Sympathetic
Encephalitis
Essential hypertension: Stress
BP = Flow x Peripheral resistance
Cardiac output = Stroke volume x Heart rate
Preload Contractility Afterload
Venous compliance
Compliance of large arteries
Inner diameter of resistant arteries
IVF volume
Na+ content Renal excretory capacity
Sympathetic Renin Ang II Aldosterone
Stress
Essential hypertension: Salt
BP = Flow x Peripheral resistance
Srdcový výdaj = Vývrhový objem x Srdcová frekvencia
Preload Contractility Afterload
Venous compliance
Large arteries compliance
Inner diameter of resistant arteries
IVF volume
Na+ content Renal excretory capacity
Renin Ang II Aldosterone
Essential hypertension:
Endothelial dysfunction
BP = Flow x Peripheral resistance
Cardiac output = Stroke volume x Heart rate
Preload Contractility Afterload
Venous compliance
Compliance of large arteries
Inner diameter of resistant arteries
IVF volume
Na+ content Renal excretory capacity
Sympathetic Renin Ang II Aldosterone
Local dilators (NO)
Endothelial dysfunction
Healthy endothelium produces endothelial factors (NO, EDHF, PGI2) which:► Inhibit platelet aggregation and adhesion► Inhibit activation of monocytes and lymphocytes► Inhibit mitogenesis and proteosynthesis► Relax vascular smooth muscle
Injured endothelium:
– Allows the subendothelial penetration of lipids and exposes highly thrombogenic tissue factors to circulating platelets
– Does not produce sufficient NO and PGI2, expresses adhesive molecules and after activation releases ET, PGH and TX, and increases superoxide production
– Superoxide produced by endothelium and fagocytes migrated subendothelial deactivates NO
– The loss of NO leads to increased platelet activation, smooth muscle proliferation and production of collagen by fibroblasts
Activated cells in the neointimal layer:
– Accumulate lipid particles (foam cells) forming thus lipid plaque
– Cause hyperplasia of the artery (smooth muscle cells)
– Increase stiffness and narrowing of the arteries and (fibroblasts)
– Induce thrombogenesis (dysfunctional endothelium and platelets)
In conditions of turbulent blood flow the plaque may rupture leading to:– Artery occlusion: brain/myocardial/leg infarction
– Form a thromboembolization
Lewis SM, Collier IC, Heitkemper MM: Medical-
surgical nursing: assessment and management of
clinical problem, ed 4, 1995, St Louis
Endothelial dysfunction
Target organ damage
Hypertension
Arterial remodelingBP and RAAS
Shiffrin, J Cell Mol Med, 2010
Complications: Target organ
damage Brain:
► Cerebrovascular incidents: Stroke, brain infarction, TIA► Neurological complications: Hypertension encephalopathy
Kidney:► Renal ischemia and loss of renal parenchyma: Chronic renal failure (fixation
of hypertension) Heart:
► Left ventricular hypertrophy (ECG, echo), IHD, fibrosis, increased stiffness,atrial dilation, heart failure
NormalLV structure and function
Hypertension HF
Overt heart failure
SmokingDyslipidaemiaDiabetes
ObesityDiabetes
LV remodelling
LVH
MISystolic
dysfunction
Diastolicdysfunction
Subclinical LV
dysfunction
Time: decades Time: months
Death
Progression from hypertension to heart failure
Influence of LVH on incident heart failure
Gardin et al Am J Cardiol 2001
Cardiovascular Health Study: a prospective, longitudinal, population-based study in 2506 subjects with 6-7 years follow-up
LV mass (g) Quartiles
Kaplan-Meier curves for incident heart failure free survival by LV mass gender-specific quartiles
Time to incident HF (days)
% free of incident HF
84
86
88
90
92
94
96
98
100
0 1000 2000
4
3
1, 2
Coronary heart disease risk factors
0
10
20
30
40
50
Rate of CHD over 8 years%
LVH
no LVH
Kannel J hypertens 1991
high cholesterol
hypertension
glucose intolerance
smoking
-
-
-
-
+
-
-
-
+
+
-
-
+
+
+
-
+
+
+
+
Clinics
Aim of investigation of hypertensive patient:
to obtain accurate and representative measurements of blood pressure
(staging), blood pressure may be low in heart failure
to identify contributory factors and any underlying cause (secondary
hypertension): search for signs of aortic coarctation, renal disease,
endocrinopathies
to assess other risk factors and quantify cardiovascular risk
to detect any complications (target organ damage) that are already present: to
search for atherosclerosis and arteriosclerosis (carotid arteries sonography,
fundoscopy), left ventricular hypertrophy, diastolic dysfunction, IHD, renal failure
to identify comorbidity that may influence the choice of antihypertensive therapy:
dyslipidemia, obesity, hyperinsulinemia and insuline resistance
=CXR, ECG, echo, ambulatory blood pressure, U, Cr and E, protein levels, glucose
levels, glucose tolerance, lipid profile
The major aim of a therapy?
To reduce mortality and extend survival
High
blood
pressure
Mortality
Marker of mortality
Primary end-point
Left ventricular hypertrophy
Myocardial fibrosis
Atherosclerosis
Endothelial dysfunction
Ischemic heart disease
Stroke
Heart failure
Secondary end-point
Only a syndrome?
Disease
Quality of life
and to increase QUALYs
Treatment
Generally, treatment should be initiated at 160/95 mm Hg and target blood
pressure values are 130/85 mm Hg
The higher risk, the more benefit from the treatment. Therefore, the threshold
values for treatment decrease with the number of comorbidities. E.g. in DM the
threshold is set to 140/90 mm Hg and target blood pressure values are 120/80
mm Hg (HOT).
Major classes of antihypertensive treatment:
► Diuretics
► ACE inhibitors and AT receptor blockers
► Beta-blockers
► Calcium antagonists
BP treatment
BP = Flow x Peripheral resistance
Cardiac output = Stroke volume x Heart rate
Preload Contractility Afterload
Venous compliance
Compliance of large arteries
Inner diameter of resistant arteries
IVF volume
Na+ content Renal excretory capacity
Sympathetic Renin Ang II Aldosterone
Parasympathetic Local vasodilators (NO)
Calcium antagonists Diuretics Beta-blockers ACE-inhibitors
Which drug is the best?
Diuretics
Cheap
Most effective in afro-american and elderly
Calcium antagonists
Cheap
Negative effects
Effective in BP lowering
Beta-blockers
Cardioprotective
Cave in DM and asthma
Effective in hyperdynamic hypertension
in young
Cause erectile dysfunction
ACE inhibitors
Cardioprotective, renoprotective
Expensive
May be used in asthma and IHD
Time to Primary OutcomeONTARGET
Years of Follow-up
Cu
mu
lative
Ha
za
rd R
ate
s
0.0
0.0
50
.10
0.1
50
.20
0.2
5
0 1 2 3 4
Telmisartan
Ramipril
# at Risk Yr 1 Yr 2 Yr 3 Yr 4
T 8542 8176 7778 7420 7051
R 8576 8214 7832 7473 7095
ONTARGET Investigators NEJM 358(15): 1547-59; 2008
2009: 28 molecules in clinical developement
2012:
Arterial hypertension2009->2012
Arterial hypertension2015 Table 1 Molecules currently or previously in development for hypertension treatment
Mode of action
Investigation for hypertension
Active/Inactive
Compound(s) (Phase of clinical investigation)
Angiotensin Converting Enzyme / Neprilysin Inhibitors
Inactive: Sampatrilat (III), Omapatrilat (III), Ilepatril (AVE-7688, IIb/III)
Angiotensin (AT1) Receptor / Neprilysin Inhibitors (ARNI)
Active: LCZ696 (Sacubitril, AHU377) (III for HT and HF)
Inactive: VNP489 (I)
Endothelin Receptor Blocker
Inactive: Darusentan (III), TBC3711 (II), Ambrisentan (2007 approved for PAH),
Macitentan (2013 approved for PAH)
Endothelin Receptor / Angiotensin (AT1) Receptor Blockers
Inactive: PS433540 (IIb)
Endothelin Converting Enzyme / Neprilysin Inhibitors
Active: SLV336 (PC), SLV338 (PC), SLV306 (daglutril, KC126115) (II)
Phosphodiesterase 3 Inhibitors
Inactive: Cilostazol (1999 approved for IC)
Phosphodiesterase 5 Inhibitors
Active: KD027 (Slx-2101) (II)
Inactive: Vardenafil (2003 approved for PAH), Tadalafil (2009 approved for PAH; II
for HT)
Vasoactive Intestinal Peptide Analogue
Active: PB1046 (II further studies probably in HF and PAH)
Natriuretic Peptide and Natriuretic Molecules
Active: PL3994 (IIa)
Inactive MK-7145 (Ib), MK-8150 (Ib)
Angiotensin AT2 Receptor Agonists
Active: Compound 21 (PC)
Inactive: LP2 (PC), CGP42112A (PC)
Mas Receptor Agonists
Inactive: AVE-0991 (PC), NorLeu3-Ang (1-7) (PC), CGEN-856 (PC), PanCyte Ang
(1-7) (PC)
Active: Hydroxypropyl-Ang (1-7) (PC)
Angiotensin Converting Enzyme 2 Supplementation / Activators
Active: rhACE2 (APN01) (II further studies in acute lung injury)
Inactive: XNT (PC), diaminazene (DIZI) (PC)
HF, Heart Failure; HT, Hypertension; IC, Intermittent Claudication; PAH, Pulmonary Arterial Hypertension;
PC, Pre-clinical phase
The “protective RAAS”
Classical RAAS
Renin
Angiotensinogen
Angiotensin I
Angiotensin II
Angiotensin II type 1 receptor
(AT1R)
Angiotensin converting
enzyme (ACE)
Aldosterone
Vasoconstriction
(systemic, renal)
Hypertrophy
Inflammation
Na+ and water
retention
Renin inhibitors
ACE inhibitors
AT1R blockers
Aldosterone receptor
antagonists
RAAS targeting therapiesCornerstone for CV risk reduction
ACEi
RI
ARB
ACEi
Novel RAAS
Renin
Angiotensinogen
Angiotensin I
Vasoconstriction
(systemic, renal)
Hypertrophy
Inflammation
Na+ and water
retention
Renin inhibitors
(Pro)Renin Receptor
antagonists
Prorenin
(Pro)Renin Receptor
PLZF
PI3K
Akt
MAPKs
Proliferation/Hypertrophy
Apoptosis
Fibrosis
Novel RAAS
Renin
Angiotensinogen
Angiotensin I
Angiotensin II
AT1R
Angiotensin
converting
enzyme (ACE)
Vasoconstriction
(systemic, renal)
Hypertrophy
Inflammation
Na+ and water
retention
Renin inhibitors
ACE inhibitors
AT1R blockers
Chymase, Tonin, Cathepsin G
Bradykinine
Inactive
Vasodilation
AT2R
Vasodilation
Apoptosis
NO production
Reduced proliferation
Neurotrophic effects
AT2R agonist
Novel RAAS
Renin
Angiotensinogen
Angiotensin I (1-10)
Angiotensin II (1-8)
AT1R
Vasoconstricti
on (systemic,
renal)
Hypertrophy
Inflammation
Na+ and water
retention
ACE,
Chymase,
Tonin,
Cathepsin G
Bradykinine
Inactive
Vasodilation
AT2R
Angiotensin 1-9
Angiotensin 1-7
ACE2
ACE2
ACE
Angiotensin III (2-8)
Angiotensin IV (3-8)
AMPA
AMPM
AT4R
(IRAP)
MASVasodilation
Anti-
proliferation
Anti-
inflammation
RAASDeleterious and protective
CombinationsCombi in 2014-SHR-ATQ
